Patients with cystic fibrosis (CF) are at risk for endocrine complications of their disease, including osteoporosis and diabetes. These complications are associated with significant morbidity and mortality in this patient population, and the underlying pathogenesis is not well understood. Recent evidence suggests that the CF transmembrane conductance regulator (CFTR) protein is expressed in human bone cells and pancreatic beta cells and may play a causative role in these disorders. A new FDA-approved medication, ivacaftor, pharmacologically potentiates CFTR activity in subjects with G551D-CFTR mutations and has been shown to improve pulmonary function and sweat chloride levels. This medication offers the unique opportunity to study the effects of improving CFTR function on bone and glucose homeostasis in humans with CF. This project is a prospective multiple cohort study, conceived and developed solely by the candidate under the guidance of her mentors, with goals to (1) investigate the effect of G551D genotype on the development of endocrine complications of CF; (2) assess change in (a) bone microarchitecture and volumetric bone mineral density using state-of-art skeletal imaging techniques and (b) measures of glucose homeostasis in subjects treated with ivacaftor compared to CF patients not receiving this medication and healthy subjects matched for age, race, and gender; and (3) investigate a bone-derived protein, undercarboxylated osteocalcin, as a novel mechanism linking CF-related bone disease and CF-related diabetes. Dr. Putman is a dual-trained adult and pediatric endocrinologist whose ultimate career goal is to become a successful, independent clinical investigator in the field of CF-related endocrine complications. During the time period of her K23 grant, she will acquire the requisite skills in clinical and translational investigation through a detailed career development plan that consists of formal course work, attendance of conferences and seminars, participation in workshops, and hands-on experience specifically in the areas of (1) endocrinology, including bone health and diabetes, (2) CF, and (3) clinical research. She will be mentored by leading investigators in the field of bone and mineral metabolism (Drs. Finkelstein and Bouxsein) and CF (Dr. Moskowitz), all of whom have considerable mentoring experience. Her advisory committee will include a team of distinguished experts in the fields of pediatric bone health, osteoporosis, CF, and diabetes. In summary, the research and mentoring plan proposed in this K23 application will test innovative hypotheses about the role of CFTR in bone and glucose homeostasis, will broaden our understanding of the endocrine complications of CF, and will provide the necessary training and investigational niche for Dr. Putman to develop a successful, independent career in clinical research.